The direction and hypotheses of Project 1 emerge from key findings that the decreases in growth hormone[unreadable] and IGF-1 are critical factors in the age-related decline in vascular density, cerebral blood flow, glucose[unreadable] metabolism and impaired performance in hippocampally-dependent tasks of learning and memory. These[unreadable] findings have led us to propose that decreases in vascular density and angiogenesis, pertubations in[unreadable] vascular reactivity, and impairments in vascular transport and secretion of key trophic factors contribute to a[unreadable] mismatch between regional metabolic demand and blood flow in aged animals: The resulting alterations[unreadable] within the vascular-glia-neuronal micro-environment impair cellular proliferation, synaptic efficacy and[unreadable] performance on hippocampally-dependent tasks of learning and memory. The following aims are[unreadable] proposed:1) Assess whether growth hormone/IGF-1 deficiency contributes to a regional reduction in capillary[unreadable] and arteriolar density, angiogenesis, and blood flow. 2) Assess whether alterations in cerebral vascular[unreadable] reactivity occur with age (the unique relationship between Em, [Ca2+]i and vessel diameter); the effects of[unreadable] aging on SR Ca2+ release events in the cerebral circulation and the mechanisms by which growth hormone[unreadable] and IGF-1 replacement therapy reverse the age-associated alterations in cerebral vascular reactivity. 3)[unreadable] Determine whether trophic factors produced by the vasculature and found to be necessary for[unreadable] hippocampally-dependent processes of learning and memory are reduced in the hippocampal[unreadable] microenvironment of aged animals and whether administration of growth hormone results in increased levels[unreadable] of these trophic factors and improved cognitive performance. These studies will use young and old animals[unreadable] and old animals treated with growth hormone that restores cognitive function and the unique model of adultonset[unreadable] growth hormone and IGF-1 deficiency developed by the Animal Core to assess the effects of a[unreadable] primary, specific deficiency of these hormones apart from aging. The results of these studies will greatly[unreadable] extend our understanding of the role of growth hormone and IGF-1 in regulation of vascular structure and[unreadable] function and the inter-relationships that occur between cerebrovasculature dysfunction and functional[unreadable] changes in the brain that are precursors to age-related disease, cognitive dysfunction and increased risk of[unreadable] dementia.